1,4-substituted-pyrimidin-2(1h)-ones

ABSTRACT

COMPOUNDS OF THE CLASS OF 1-SUBSTITUTED-4-ARYL-PYRIMIDIN-2(IH)-ONES, METHODS AND INTERMEDIATES FOR PREPARATION OF SAID COMPOUNDS, AND PHARMACEUTICAL METHODS AND COMPOSITIONS BASED ON SAID COMPOUNDS AND USEFUL IN THERAPY, FOR EXAMPLE, IN THE TREATMENT OF INFLAMMATION IN ANIMALS.

United States Patent ABSTRACT OF THE DISCLOSURE Compounds of the classof 1substituted-4aryl-pyrimidin-2(1l-I)-ones, methods and intermediatesfor preparation of said compounds, and pharmaceutical methods andcompositions based on said compounds and useful in therapy, for example,in the treatment of inflammation in animals.

Claims This application is a division of Ser. No. 779,200, filed Nov.26, 1968, now US. Pat. 3,663,698.

The present invention relates to methods and compositions employing1,4-disubstituted-pyrimidin-Z(1H)-ones, more particularly,l-substituted-4 aryl-pyrimidin-2(1H)- ones, and having utility intherapy, for example, in the treatment of inflammation in animals. Theinvention also relates to certain novel l-substituted-4aryl-pyrimidin-2(1I-I)-ones and also to intermediates and processes for preparation ofl-substituted-4 aryl-pyrimidin-2(1H)-ones.

The compound which is 1-methyl-4-phenyl-pyrimidin- 2(lH)-one has beenheretofore disclosed by G. Mannich et al. Ber. 55, 365 (1922). Noutility for said compound has been to our knowledge disclosed.

The present invention provides in one aspect thereof the method oftreating inflammation in animals comprising administering thereto apharmacologically effective amount of a compound of formula I:

C=O (Rh. I

l RI! R" is Z-thienyl, phenyl or substituted phenyl of the formulawherein Y is halo, preferably of atomic weight no greater than 80;

lower alkyl, preferably of from 1 to 4 carbon atoms; or lower alkoxy,preferably of l to 4 carbon atoms; and Y is hydrogen, halo, lower alkylor lower alkoxy.

A procedure A suitable for preparation of the great majority of thecompounds of formula I involves a Step A reaction of a1-substituted-pyrimidin-2(1I-I)-one of formula II wherein R and n are asabove-defined and R is the same as R excluding carboxyalkyl andpropargyl, with an aryl lithium compound or an arylmagnesium haliderespectively of the formulae III:

RLi (IIIa) or R"MgX (IIIb) wherein X is a Grignard halogen, e.g., chloroand bromo, preferably chloro, and R" is as above-defined, the preferredcompound III being R"Li, followed by hydrolysis in a conventional mannerto obtain novel 3,4-dihydropyrimidin-2(1H)-ones of the formula IV:

n H a wherein R, R R" and n are as above-defined, said com pounds offormula IV then being subjected in a Step AA reaction to oxidization ina known manner, e.g., with an alkali metal permanganate or manganesedioxide, to obtain the corresponding l-substituted pyrimidin-2(lI-I)-ones of the formula Ia:

in (V) l wherein R, R R" and n are as above defined.

The production of compounds Ia by Procedure A involves the Step Areaction of a compound II with a compound IIIa or IIIb which may becarried out in a conventional manner in the presence of an inert organicsolvent and at temperatures in the range of C. to 60 C., preferably C.to 45 C., followed by hydrolysis in the known manner. Preferred solventsare those customarily employed in Grignard reactions, more preferablythe ethers including, by way of illustration, tetrahydrofuran, dioxane,dimethoxyethane and diethyl ether. The particularly preferred compoundof formula III for use in Step A is an aryl lithium compound of formula11121. The product compounds IV from Step A may be isolated byconventional procedures in suitable form for use independently orin StepAA, as desired.

Completion of the Procedure A for producing compound la in Step AAinvolves subjecting a compound IV to oxidation which may be convenientlycarried out at temperatures in the range of from C. to 150 C.,preferably 40 C. to 100 C. Suitable oxidizing agents are those ofconventional types, preferably an alkali metal permanganate such assodium or potassium permaganate, or manganese dioxide of the well knownactive or oxidizing grades. The particularly preferred oxidizing agentfound to reduce side reactions is manganese dioxide. The oxidation iscarried out in a suitable inert liquid medium which is conveniently anorganic solvent of conventional type, preferably dioxane, acetone,benzene, xylene and the like. The products compounds Ia may be isolatedfrom the Step AA reaction by working up by conventional procedures.

Several of the l-substituted-pyrimidin-2(lH)-ones employed as startingmaterial in Step A are known compounds heretofore described in theliterature, e.g., by D. I. Brown et al., J. Chem. Soc. 1965, 4911. Suchother of said compounds II which are not specifically known may beprepared from known materials by established procedures. Similarly, thecompounds 111a and IIIb are well known or can be readily prepared.

The preparation of compounds Ib by Procedure B involving reaction of the1-metallo-4-aryl-pyrimidin-2(1H)- one of formula V with an organichalide of formula VI is conveniently carried out at temperatures in therange of from 10 C. up to about 100 C., preferably at about roomtemperature (20 C.) or at elevated temperature up to 80 C. The reactionis carried out in an inert solvent which may be any of severalconventional types such that the solvent is conveniently the solventemployed in preparation of the starting metallo compound V. The organichalides VI are well known or readily prepared, and are preferablyemployed in the form of the bromide, chloride or iodide.

The l-metallo salts of formula V employed in Pro cedure B are readilyprepared by treating the corresponding1-unsubstituted-4-aryl-pyrimidin-2(1H)-ones in a conventional mannerwith reagents commonly employed for preparing alkali metal salts, e.g.,sodium hydride and alkali metal alkoxides such as sodium methoxide,sodium ethoxide, potassium methoxide, and potassium ethoxide. Suchpreparation of the l-metallo salts which is preferably the sodium saltis carried out in an inert organic solvent which is preferably any ofseveral of the conventional solvents conveniently suitable for both thesalt preparation and use in the reaction of Preparation B. Such solventsinclude, by way of illustration, dimethylacetamide, dimethylformamide,and dioxane, more usually dimethylacetamide.

The compounds of formula I in which R is carboxyalkyl are desirablyprepared from the corresponding lower (1 to 4 carbon atoms) alkyl esterby subjecting said ester to hydrolysis in a conventional manner,preferably by treating with an aqueous alkali metal hydroxide solutionin a lower alkanol solvent at room to reflux temperature in thetemperature range of 20 C. to 90 C. The appropriate esters may beprepared by the reaction of Procedure B, as above-described, by reactingcompound V with a carbalkoxyalkyl halide of formula Vla.

R 'X (Vla) wherein X is as above-defined and R represents carb- (lowerof 1 to 4 carbon atoms)alkoxy(lower of 1 to 5 carbon atoms)alkyl, e.g.,

CH CH-C OO CH2CH3 or C HzC O O CIIzCIIs.

The l unsubstituted-4-aryl-pyrimidin-2(1H)-ones employed in preparationof the l-metallo salts of formula V represent a class of compoundgenerally disclosed in the literature, e.g., J. Chem. Soc. 1951, 2323.Those l-substituted-4-aryl-pyrimidin-2(lH)-ones not specificallydisclosed may be prepared from known materials by disclosed procedures,for example, as exemplified hereinafter in Examples 6-11. See also A.Pasteur et al., Bull. Soc. Chim., 1965 (8), 232832.

Procedures A and B are well suited to preparation of compounds useful inthe invention. We have preference for Procedure B for the generalsignificances of R in formula I while Procedure A is preferred insituations where R" represents substituted phenyl or thienyl. However,the individual preferences of those skilled in the art may vary based onconventional consideration such as overall process efiiciencies, costand availability of the starting materials, equipment factors and thelike.

Certain of compounds I as represented by those in which R isdialkylaminoalkyl will have a basic nitrogen atom and thus may form acidaddition salts, and may be produced and isolated as such acid additionsalts, as desired or required. It will be evident that pharmaceuticallyacceptable acid addition salts not materially affecting thepharmacological effect of compounds I are also within the scope of thepresent invention. Such pharmaceutically acceptable salts may include,by way of illustration, the hydrochloride, fumarate, maleate, formate,acetate, sulfonate and malonate. The acid addition salts of the subjectcompound I may be produced from the corresponding free bases byconventional procedures known in the art.

The compositions of the invention are pharmaceutically useful becausethe compounds of formula I exhibit pharmacological activity in animals.In particular, the compositions are useful in relieving inflammatorymanifestations in animals because compounds I are anti-inflammatoryagents, as indicated, for example, by the Carrageenaninduced edema teston rats on oral administration at doses of l0-150 mg./kg. Thecompositions of the invention are also useful for relieving pain inanimals because compounds I are also analgesics, as indicated, forexample, by application of pressure to the yeast-inflamed foot of therat on oral administration at doses of l0l50 mg./kg. The dosage ofcompounds I will, of course, vary depending upon the compounds used andthe mode of administration. However, in general, satisfactory resultsare obtained when administered at a daily dosage of l milligrams to 150milligrams per kilogram of body weight, preferably given in divideddoses 2 to 4 times a day, or in sustained release form. For most mammalsthe administration of from to 1500 milligrams of a compound of formula Iper day provides satisfactory results and dosage forms suitable forinternal administration comprise from about 15 milligrams to 750milligrams of the compound in admixture with a solid or liquidpharmaceutical carrier or diluent.

For the above uses, the composition of the invention may be formulatedin a conventional manner to contain an effective dose of a compound offormula I as active ingredient together with an inert pharmaceuticallyacceptable carrier adapted to provide a composition suitable for eitheroral administration or for administration parenterally in the form of aninjectable solution or suspension.

In general, the preferred compositions are those adapted for oraladministration and conventional forms for this purpose are suitable,such as tablets, dispersible powders, granules, capsules, syrups,elixirs and the like. Such compositions may be prepared according to anymethod known in the art for the manufacture of pharmaceuticalcompositions, and such compositions may contain one or more conventionaladjuvants, such as sweetening agents, flavoring agents, coloring agentsand preserving agents, in order to provide an elegant and palatablepreparation. Tablets may contain the active ingredient in admixture withconventional pharmaceutical excipients, e.g., inert diluents such ascalcium carbonate, sodium carbonate, lactose and talc, granulating anddisintegrating agents, e.g., starch and alginic acid, binding agents,e.g., starch, gelatin and acacia, and lubricating agents, e.g.,magnesium stearate, stearic acid and tale. The tablets may be uncoatedor coated by known techniques to delay disintegration and adsorption inthe gastro-intestinal tract and thereby provide a sustained action overa longer period. Similarly, suspensions, syrups and elixirs may containthe active ingredient in admixture with any of the conventionalexcipients utilized for the preparation of such compositions, e.g.,suspending agents (methylcellulose, tragacanth and sodium alginate),wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylenesorbitan monooleate) and preservatives (ethyl-p-hydroxybenzoate).Capsules may contain the active ingredient alone or admixed with aninert solid diluent, e.g., calcium carbonate, calcium phosphate andkaolin. The preferred pharmaceutical compositions from the standpoint ofpreparation and ease of administration are solid compositions,particularly hard-filled capsules and tablets.

A representative formulation is a tablet prepared by conventionaltabletting techniques and containing the following ingredients:

Ingredients: Weight (mg) l-Methyl-4 phenyl-pyrimidin-2(lH)-one 50Tragacanth Lactose 197.5 Corn starch 25 Talcum l5 Magnesium stearate 2.5

Compositions for parenteral administration may be formulated by wellknown methods to contain an effective amount of a compound I as activeingredient in a conventional inert carrier or suspension or solventmedium, together with other additives such as dispersing agents, wettingagents, buffering agents and other conventional ingredients, as desired.

A representative formulation for intravenous administration is asolution prepared by standard procedures and containing the followingingredients:

Ingredient: Weight (percent) 1-Methyl-4-phenyl-pyrimidin-2(1H)-one 5Ethanol, U.S.P. 1020 Propylene Glycol -25 Water for Injection 55-75Sodium Chloride to make isotonic. Buffer Agent to adjust pH.

butyl, especially t-butyl. It has also been found that compounds offormula I in which R is alkyl other than methyl are useful asanti-convulsants, more particularly the compounds in which R representsan alkyl of at least 3 carbon atoms, and especially when R is a branchedalkyl, e.g., isopropyl and tertiary butyl. The usefulness of suchcompounds as anticonvulsants is indicated, for example, by an inhibitionof maximal electroshock induced convulsion in mice according to themethod of TOman et al., I Neurophysiol 9: 231 (1946) on interperitonealadministration at dosages of 50-200 mg./ kg. The particular dosages foruse as anti-convulsants will vary depending upon standard factors suchas the particular compound employed and mode of administration. However,in general, satisfactory results may be obtained when administered at adaily dose of from 4 milligrams to 200 milligrams per kilogram of bodyweight. For most mammals the administration of from 280 to 2000milligrams of the compound per day provides satisfactory results anddosage forms suitable for internal administration comprise from about 70to 1000 milligrams of the compound. Compositions adapted for inhibitingconvulsion in animals will contain the active compound together with aninert carrier or diluent adapted for either oral or parenteraladministration according to the same conventional formulations andprocedures applicable for other uses of the compounds of formula I, asabove described.

The 3,4-dihydropyrimidin-2(1H)-ones of formula IV also are useful asanti-inflammatory and analgesic agents as indicated by theabove-referred to animal tests. Such compounds may be administered toanimal in the conventional forms and by the known methodsabove-indicated as suitable for the compounds of formula I. Dailydosages of the compounds of formula IV for animals generally rangebetween 2-250 mg./kg. of body weight with daily dosages for mammalsbeing in the range of -l20 to 2500 milligrams and individual dosesranging from 30 to 1250 milligrams. The compounds of formula IV are lessactive pharmaceutically than their corresponding compounds of formula Ias reflected by a comparison of the above-indicated dosages although itwill be evident that comopunds IV have the feature of being subject topreparation by Step A of procedure A without the necessity of theadditional reaction of Step AA.

The following examples show representative com pounds encompassed withinthe scope of this invention and the manner in which such compounds areprepared. However, it is to be understood that the examples are forpurposes of illustration only and are not intended as in any waylimiting the scope of the invention.

'EXA'MPLE 1a 1-Methyl-4-phenyl-3,4-dihydropyrimidin-2(lH)-one C=O m To asolution of 5.5 g. of l-methyl-Z-pyrimidone dissolved in 300 ml.dimethoxyethane and' cooled to 0 is added dropwise with stirring 25 ml.of a 2.1 N solution of phenyl lithium in hexane. The mixture is stirredfor an additional 3 hours at 0, poured into water, and concentrated invacuo to remove hexane and dimethoxyethane. The resulting crystallineprecipitate is washed with water and dried to obtainl-methyl-4-phenyl-3,4-dihydropyrimidin-2(lH)-one, mp. l28-l3l C.

7 EXAMPLE 1b 1-Methyl-4-phenyl-pyrimidin-Z(1H)-one To a mixture of 1.88g. of l-methyl-4-phenyl-3,4-dihydropyrimidin-2(lH)-one dissolved in 150ml. of dioxane is added dropwise with stirring 22 ml. of a potassiumper- EXAMPLE 2 l-Methyl-4-(2-thienyl)-pyrimidin-2(1H)-one Step A:Preparation of 1-methyl-4-(2-thienyl)-3,4-dihydropyrimidin-2(lH)-one.-To a solution of 4.5 g. of abin 100 ml. absoluteether is added 31 ml. of 1.6 molar butyllithium (in hexane). The mixtureis refluxed for 5 hours under dry nitrogen and there is added 100 ml. ofabsolute dimethoxyethane to displace the ether. The to a preparedsuspension of 5.5 g. N-methylpyrimidone in 500 ml. dimethoxyethane understirring and the resulting mixture stirred for 30 minutes. There is thenadded 50 ml. of water and the mixture is evaporated to A of its volume.An additional 150 ml. of water is added and a crystalline precipitatefiltered off, washed with water, dried under high vacuum, and purifiedby crystallization from methanol to obtain l-methyl-4-(2-thienyl)-pyrimidine-2(1H)-one, m.p. 145 C.-l47 C.

Step B: Preparation of l-methyl-4-(2-thienyl)-pyrimidin-2( lH)-one.To asuspension of 4.6 g. of l-methyl-4-(Z-thienyl)-3,4-dihydropyriclimidin-2(1H)-one in 250 ml. absolutebenzene is added 4 g. of manganese dioxide and the resulting mixturerefluxed for 24 hours under stirring. After cooling to room temperaturethere is added 100 ml. of methylene chloride/ methanol (1:1) followed byfiltering off the MnO and evaporating the filtrate under re ducedpressure. Purification by crystallizing the residue from methanol/ether(1:2) yields l-methyl4-(2-thienyl)- pyrimidin-2( lH)-one, m.p. 221224 C.

solute thiophene dissolved remaining solution is added dropwise 7EXAMPLE 3 v 4-Pheny1- l-tert.butyl-3 ,4-dihydropyrimidin-2 (-1 H -oneCll;-( |3-CH;

To a solution of 15.2 g. of l-tert.butyl-pyrimidin- 2( 1H)-one in 800ml. of absolute tetrahydrofuran is added dropwise ml. of a 2.14 molarsolution of phenyllithium with stirring at room temperature. Theresulting mixture is stirred for two hours at room temperature, andevaporated in vacuo to dryness. The residue is dissolved in 200 ml. ofmethylene chloride, washed three times with ml. of water, dried overanhydrous sodium sulfate and evaporated in vacuo to obtain4-phenyl-l-tert.butyl-3,4-dihydropyrimidin2(1H)-one, m.p. 117 C.-l 18 C.

EXAMPLE 4 4-Phenyl-1tert.butyl-pyrimidin-2 1H) -one To a solution of 7g. of 4-phenyl-1-tert.butyl-3,4-dihydropyrimidin-2(1H)-one in 500 ml. ofabsolute benzene is added 7 g. of manganese dioxide. The resultingmixture is refluxed for 16 hours, manganese dioxide filtered ofiF andthe resulting solution evaporated in vacuo to remove solvent. Theresidue is crystallized from petroleum ether to obtain4-phenyl-1-tert.butyl-pyrimidin-2(1H)-one, m.p. C.-126 C.

EXAMPLE 5 The preceding Examples illustrate preparation according to theProcedure A hereinbefore disclosed. By following the two step ProcedureA as illustrated by the Examples, and substituting the appropriatestarting materials in approximately equivalent amounts, one is able toprepare the following:

4-Phenyl-l-propyl-pyrimidin 2(lH) one, m.p. 129- (Crystallization from:ethanol) (Reaction Solvent: toluene)l-Ethyl-4-phenyl-pyrimidin-2(lH)-one, m.p. l38-l42 C. (Crystallizationfrom: methylene chloride/diethyl ether) (Reaction solvent: benzene) StepA: l-Isopropyl 4 phenyl 3,4 dihydropyrimidin- 2(lH)-one, m.p. 117119 C.

(Crystallization from: ethylacetate/pentane) (Reaction solvent:dimethoxy ethane) Step AA: l-lsopropyl-4-phenyl-pyrimidin 2(ll-l) one,

m.p. l46-l49 C.

(Crystallization from: methylene chloride/diethyl ether) (Reactionsolvent: benzene) EXAMPLE 6 l-Isopropyl-4-phenyl-pyrimidin-2(1H) -one(by Procedure B) Step A: Preparation of sodium benzoylacetaldehyde. Asodium ethoxide solution prepared by dissolving 5.8 g. of sodium in 100ml. ethanol is evaporated in vacuo, and there is then added 500 absolutediethyl ether. There is then added with stirring a solution of 20 ml. ofethyl formate and 30 g. of acetophenone dissolved in 200 ml. of diethylether. The resulting mixture containing a white precipitate is stirredfor 1 hour, filtered, and the precipitate washed with diethyl ether anddried under high vacuum at 80 C. for 4 hours to obtain sodiumbenzoylacetaldehyde.

Step B: Preparation of 2-amino4-phenyl pyrimidine.- To a suspension ofthe sodium salt produced in Step A, above, in 450 ml. of pyridine isadded 45 g. of guanidine nitrate, and the resulting mixture is refluxedfor 7 hours. The resulting mixture is evaporated in vacuo to dryness,the residue treated with 100 ml. of 2N sodium hydroxide, filtered, theresidue washed with 2N sodium hydroxide and then with water, anddissolved in 100 m1. of 2N hydrochloric acid. The resulting solution ismade alkaline and then filtered to separate the resulting precipitatewhich is washed generously with water and then dried in high vacuum at80 C. to obtain 2-amino-4-phenylpyrimidine, m.p. 162-165 C.

Step C: Preparation of 4 phenyl-pyrimidin 2(1H) one-To a solution of42.6 g. of 2-amino-4-phenyl-pyrimidine dissolved in 2.5 liters of 6-7%sulfuric acid and cooled to -l0 C. by an ice sodium chloride mixture isadded dropwise a solution of 36 g. of sodium nitrite in 100 ml. ofwater. The resulting mixture is stirred for 2 hours at O-l0 C., and thenallowed to stand 20 hours at 20 C. The resulting mixture is filtered,treated with concentrated ammonium hydroxide until pH 3, and theresulting precipitate filtered from the mixture, washed generously withwater and dried in high vacuum at 80 C. to obtain4-phenyl-pyrimidin-2(1H)-one, m.p. 238244 C.

Step D: Preparation of 1-isopropyl4-phenyl-pyrimidin-2(lH)-one.-To asolution of g. of 4-phenyl-pyrimidin-2(1H)-one in 400 ml. ofdimethylacetamide is added 2.4 g. of sodium hydride (57% in mineralsuspen sion washed with pentane prior to use). The resulting mixture isstirred for /2 hour at room temperature and there is added 7.2 g. ofisopropylbromide. This mixture is heated at 60-65 C. for 10 hours andevaporated in vacuo to dryness. The residue is dissolved in chloroform,and the solution washed three times with 100 ml. of water. The organicphase is dried over anhydrous sodium sulfate, evaporated in vacuo, andthe residue crystallized from methylene chloride/pentane (1:1) to obtainl-isopropyl- 4-phenyl-pyrimidin-2(lH)-one, m.p. 146-149" C.

10 EXAMPLE 7 Following the procedure of Step D of Example 6, andemploying equivalent amounts, 4-phenyl-pyrimidin- 2(1H)-one is reactedfirst with sodium hydride and then with bromoethylacetate to obtain oncrystallization from methylene chloride/pentane 1 carbethoxymethyl 4phenyl-pyrimidin-2(1H)-one, m.p. 125-127 C. This product (2.6 g.) isdissolved in 30 ml. of methanol and the resulting solution treated byaddition of 20 ml. of 2N sodium hydroxide followed by refluxing for 5hours. The resulting mixture is evaporated in vacuo to remove ethanol,and the remaining solution treated with sutficient 2N hydrochloric acidto bring to pH 4 and obtain a precipitate which is filtered off, washedgenerously with water and dried in high vacuum at C. to obtainl-carboxymethyl-4-phenyl-pyrimidin-2 1H -one,

m.p. 228-231" 0. EXAMPLE 8 1- l-carboxyethyl -4phenyl-pyrimidin-2 1H)-one EXAMPLE 9 1-Methyl-4(4-chlorophenyl)-pyrimidin-2(1H)-one Followingthe procedure of Steps A-D of Example 6, and substituting theappropriate corresponding starting materials in approximately equivalentamounts, there is obtained in Step D (employing methyl iodide) oncrystallization from methanol crystals of1-methyl-4-(4-chlorophenyl)-pyrimidin-2(1H) 0ne, mp. 227-230" C.

-1 1 EXAMPLE 1,6-Dimethyl-4-phenyl-pyrimidin-2(1H)-one I CH3 Followingthe procedure of Ste'p's"AD of Example 6, and substituting theappropriate corresponding starting materials inapproximately equivalentamounts, there is obtainedin Step D on Crystallization from methylenechloride/diethyl ether crystals of 1,6-dimethyl-4-phenyl-'pyrimidin-(lH)-ones, m.p. 163-165 C.

" JEXAMPLE 11 1-allyl-4-phenyl-pyrimidin 2(1H)-one, m.p. 110-113 C.(Crystallization from methylene chloride/pentane) (Reaction solvent:dimethylacetamide) 1(dimethylaminopropyl)-4-phenyl-pyrimidin-2(1H)onemaleate, m.p. ISO-152 C.

(Crystallization from methylene chloride) (Reaction solvent:dimethylacet-amide) 4-phenyl-1-propargyl-pyrimidin-2(1H)-one, mp. 158-(Crystallization from methylene chloride/diethyl wherein R is alkyl of 1to 3 carbon atoms; n is 0 to 2;

R is branched alkyl of 3 to 5 carbon atoms, allyl, methallyl, propargyl,dialkylaminoalkyl in which each alkyl is of 1 to 4 carbon atoms,carboxyalkyl of 2 to 5 total carbon atoms, carbalkoxyalkyl in which thealkoxy is of 1 to 4 carbon atoms and the alkyl is of 1 to 5 carbon atomsor benzyl; is 2-thienyl, phenyl or substituted phenyl of the formula:

wherein Y is halo of atomic weight no greater than 80, alkyl of 1 to 4carbon atoms or alkoxy of 1 to 4 carbon atoms; and

Y is hydrogen, halo of atomic weight no greater than 80, alkyl of 1 to 4carbon atoms or al'koxy of 1 to 4 carbon atoms.

2. A compolnd of claim 1 in which R is isopropyl. 3. The compound ofclaim 2 in which R" is unsubstituted phenyl and n is 0.

4. A compound of claim 1 in which R is tertiary butyl.

5. The compound of claim 4 in which R" is unsubstituted phenyl and n is0.

6. A compound of the formula:

C==O (R)u I wherein R is alkyl of 1 to 3 carbon atoms; n is 0 to 2;

R is alkyl of 1 to 5 carbon atoms, allyl, methallyl, benzyl ordialkylaminoalkyl in which each alkyl is of 1 to 4 carbon atoms,

R" is Z-thienyl, phenyl or substituted phenyl of the formula:

wherein Y is halo of atomic weight no greater than 80, alkyl of 1 to 4carbon atoms or alkoxy of 1 to 4 carbon atoms; and

Y is hydrogen, halo of atomic weight no greater than 80, alkyl of 1 to 4carbon atoms or alkoxy of 1 to 4 carbon atoms.

7. A compound of claim 6 in which R" is unsubstituted phenyl.

8. A compound of claim 7 in which n is O. 9. A compound of claim 6 inwhich R is alkyl. 10. A compound of claim 9 in which R is branchedalkyl.

References Cited Mannich et al.; C. A. 16: 2498-9 (1922).

NICHOLAS S. RIZZO, Primary Examiner .R. V. R'USH, Assistant Examiner US.Cl. X.R. 260-2565 R

